ABSTRACT: Irinotecan (Camptosar) is a topoisomerase I inhibitor with demonstrated antitumor activity against a wide variety of malignancies. Phase II studies have shown that this agent has significant single-agent activity against both chemotherapy-naive and fluorouracil (5-FU)-refractory colorectal cancer. Phase III studies now indicate that irinotecan/5-FU/leucovorin combinations have antitumor activity superior to standard 5-FU/leucovorin regimens alone. These irinotecan-based combinations are now entering clinical trials for the adjuvant treatment of resected stage III colon cancer. It is hypothesized that the superior antitumor activity of these irinotecan-based combinations seen in the metastatic setting will translate into improved survival and increased cure rates in these earlier-stage patients. [ONCOLOGY 14(Suppl 14):47-50, 2000]

Localized or local-regional colon cancer
is potentially curable by surgery alone. If all gross disease is resected, then
the success or failure of the operation, and hence the ultimate cure and
survival of the patient, will depend upon whether or not micrometastases were
already present at the time of surgery, thereby rendering the procedure more
palliative than curative. If it could be determined that no micrometastases were
present after all gross disease is removed, then the patient could be considered
cured and no further therapy of an adjuvant nature would be necessary.

Given the current limitations of technology for detecting
micrometastases, treatment decisions are currently based on the probability of
microscopic cancer being present, and on the relative effectiveness of available
cytotoxic chemotherapy. Stage I and II colon cancer patients have a relatively
low probability of harboring micrometastases, and thus have a relatively high
probability of being cured by surgery alone. Adjuvant chemotherapy has not
consistently been shown to improve survival in these patients, and is not, at
this time, routinely recommended. However, lymph node-positive, or stage III,
patients have a substantial risk of having microscopic metastatic disease at the
time of resection. Looking back at historical controls from the era prior to
chemotherapy, a roughly 40% to 50% cure rate for stage III colon cancer patients
was seen with surgery alone,[1] indicating that slightly more than half of
patients did in fact have microscopic metastatic disease at the time of
resection.

Initial attempts at adjuvant therapies following stage III colon
cancer surgery were not successful,[2-4] and until the late 1980s expectant
observation was the standard of care following resection for these patients.[5]
Studies carried out by the North Central Cancer Treatment Group (NCCTG),[6]
later confirmed by larger studies conducted by the National Cancer Institute
(NCI) Intergroup,[7] established a 12-month regimen of fluorouracil (5-FU) plus
levamisole as the first effective adjuvant treatment of colorectal cancer.

A subsequent Intergroup study was done comparing this 52-week
regimen of 5-FU plus levamisole to 5-FU plus leucovorin, either on a weekly
schedule for 32 weeks, a daily x 5 schedule for 28 weeks, or a daily x 5
schedule for 28 weeks with concurrent levamisole.[8] Results of this trial are
summarized in Table 1. The
5-FU/leucovorin regimens were found to be at least as good as the longer
5-FU/levamisole treatment. The 5-FU/leucovorin/levamisole combination was found
to be more toxic without increasing efficacy relative to the 5-FU/leucovorin
regimens. These 5-FU/leucovorin regimens can therefore be regarded as the
current standard of care. They represent a substantial improvement over surgery
alone, with approximately two-thirds of stage III patients now being cured.
One-third of stage III patients, however, can be expected to have recurrence of
disease and ultimately die of their disease. The need for improved adjuvant
therapies for these patients is clear.

Irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor
that has demonstrated substantial antitumor activity in both chemotherapy-naive
and 5-FU-refractory colorectal cancer. In a phase II trial involving 41
colorectal cancer patients with no prior chemotherapy, Conti et al demonstrated
a 32% major objective response rate, with an additional 44% of patients
achieving stable disease.[9] The median duration of response in this study was 8
months, and median survival was 12 months. Very similar results were obtained in
a parallel study performed at the Mayo Clinic.[10] These results suggested that
while irinotecan had substantial antitumor activity, the overall response rates,
durations of response, and survivals were similar to those seen with currently
available 5-FU-based regimens. Another phase II trial, reported by Rothenberg
et al, indicated that irinotecan also had substantial antitumor activity in
patients with 5-FU-refractory colorectal cancer.[11] These activity rates were
subsequently confirmed in a series of multicenter trials.[12]

The demonstration of activity of irinotecan in cancers that were
refractory to 5-FU, along with the radically different mechanism of actions
between irinotecan and 5-FU, suggested that a combination regimen permitting
concurrent administration of these agents might have superior antitumor activity
to either agent alone. Two concerns at the time when these combinations were
first being developed were whether there would be negative pharmacokinetic
interactions between these two agents and whether overlapping toxicities would
make concurrent administration intolerable.

To address these issues, a phase I study was undertaken at
Memorial Sloan-Kettering Cancer Center in which escalating doses of 5-FU were
added to fixed weekly doses of irinotecan and leucovorin.[13] The result of this
phase I study is a regimen in which full-dose irinotecan at 125 mg/m2
by 90-minute infusion is followed by leucovorin at 20 mg/m2
by IV bolus and then by 5-FU at 500 mg/m2 by IV
bolus. All drugs are given weekly for 4 consecutive weeks followed by a 2-week
rest. Pharmacokinetic studies performed during this phase I study indicated that
there was no substantial pharmacokinetic interaction between 5-FU and
irinotecan. The dose-limiting toxicities were neutropenia and diarrhea, both of
which appeared to be manageable.

To assess the appropriateness of concurrent use of
irinotecan/5-FU/leucovorin, a phase III trial was undertaken. The results of
this multicenter trial have now been reported.[14] This trial was conducted at
71 sites throughout the United States, Canada, Australia, and New Zealand. It
was a prospective, open-label, multicenter, randomized phase III study to
evaluate the efficacy and safety of irinotecan/5-FU/leucovorin vs 5-FU and
leucovorin as first-line therapy for patients with metastatic colorectal cancer.

Patients were stratified by performance status, age, time from
initial diagnosis, and whether or not they had received prior adjuvant therapy.
Three treatment arms were employed. One arm was the aforementioned
irinotecan/5-FU/leucovorin combination. One arm was a standard regimen of 5-FU
and leucovorin, with 5-FU given at 425 mg/m2 by
IV bolus and leucovorin at 20 mg/m2 by IV
bolus, each given for 5 consecutive days repeated every 28 days. The third
treatment arm was irinotecan alone given at 125 mg/m2
by 90-minute infusion weekly for 4 weeks followed by a 2-week break. This last
arm was included in order to evaluate the safety and efficacy of single-agent
irinotecan in a multicenter setting.

It is noteworthy that this study began accrual at approximately
the same time that irinotecan received accelerated approval from the US Food and
Drug Administration for use in 5-FU-refractory colorectal cancer. This
effectively created a crossover design in the study, since patients receiving
5-FU/leucovorin now had the option of obtaining irinotecan commercially as
salvage therapy, and patients receiving irinotecan as first-line therapy
logically received 5-FU-based therapy as a salvage treatment when clinical
conditions permitted.

The entry criteria for the study were standard phase III
criteria. Patients were required to have measurable metastatic colorectal
cancer. They were required to have no prior chemotherapy for metastatic disease.
Prior adjuvant chemotherapy was permitted if the patient had remained
disease-free for 1 year or more following the completion of adjuvant therapy.
Patients were required to have an Eastern Cooperative Oncology Group (ECOG)
performance status of 0 to 2 and adequate hepatic, renal, and bone marrow
function.

Efficacy results are shown in Table
2. The objective response rate, time to treatment failure, and overall
survival were all statistically significantly superior in those patients
receiving irinotecan/5-FU/leucovorin vs 5-FU and leucovorin alone. Of note,
while the toxicity profiles varied between treatment arms, the overall incidence
of clinically significant toxicity was not substantially different between the
treatment arms (Table 3). While grade 3/4
diarrhea was more common in the irinotecan/5-FU/leucovorin arm than in the
5-FU/leucovorin arm, grade 4 neutropenia and neutropenic fevers were more common
with standard 5-FU/leucovorin than with the irinotecan-containing combination.
Overall, the incidence of treatment-related deaths was 1% in each arm.

A similar study has been conducted in Europe.[15] In this
particular trial, clinicians selected their preference from two different 5-FU
and leucovorin schedules, and then patients were treated on that 5-FU/leucovorin
schedule with or without irinotecan. Again, superior antitumor activity for the
irinotecan/5-FU/leucovorin combination was seen. In this trial, the toxicity of
the irinotecan-containing regimens was somewhat greater than the 5-FU/leucovorin
regimens. However, the difference in survival was again statistically
significant in favor of the irinotecan/5-FU/leucovorin combination.

Irinotecan has been shown to be an effective second-line agent
for metastatic colorectal cancer, with a randomized trial now demonstrating a
survival advantage for treatment with irinotecan over best supportive care.[16]
Ultimately, however, all patients treated in this manner are likely to die of
their disease. Likewise, while irinotecan/5-FU/leucovorin combinations represent
a step forward in the first-line treatment of metastatic disease, these regimens
are not curative in the standard metastatic setting. Micrometastatic disease in
the adjuvant setting, however, is the one scenario in which systemic
chemotherapy for colorectal cancer can be curative. Since the success of
treatment depends on the degree of antitumor activity, regimens with higher
antitumor response rates could logically be expected to provide superior results
in the adjuvant setting. Furthermore, it would seem that if 5-FU could eradicate
one population of cells and irinotecan could eradicate yet another population of
cells, the chance of rendering the patient disease free would be increased.

The only way to test this hypothesis is in a randomized phase
III trial. For this reason, such a study has now been activated through the NCI
Intergroup mechanism. Intergroup study C89803 is now accruing patients with
stage III resected colon cancer. Patients are randomized to receive either
standard weekly 5-FU and leucovorin or to receive irinotecan/5-FU/leucovorin in
the doses and schedule outlined in Figure 1.

It is hoped that the improved response rate and overall survival
seen with irinotecan/5-FU/leucovorin in the metastatic setting will be
translated to improved survival and an increased cure rate in the adjuvant
setting, thereby moving irinotecan from its current strictly palliative role
into a realm in which it is actually saving lives.

It must be emphasized, however, that until this hypothesis is
adequately tested in this phase III study, use of irinotecan-containing regimens
in the adjuvant setting remains investigational. Patients eligible for
enrollment in this trial should be strongly encouraged to participate. It is
only through the completion of randomized clinical trials such as this one that
new treatment ideas can be properly tested, so as to determine whether or not
they truly constitute a step forward in the standard of care.